HYBRIGENICS

Research

Deubiquitinating Enzymes +

Ubiquitin is a small regulatory protein that directs protein recycling. Ubiquitin can be attached to proteins, labeling them for destruction by the proteasome (protein complex that degrades and recycles unneeded proteins).

Deubiquitinating enzymes (DUBs) behave mainly like recycling enzymes preventing ubiquitinated proteins from being degraded by the proteasome. When their substrates are oncoproteins, their role is in fact detrimental. Inhibiting such DUBs results in the forced degradation of those oncoproteins. This is the rationale supporting Hybrigenics' anticancer research in the ubiquitin-proteasome pathway, upstream of the proteasome1, 2, 3.

DUBs belong to the ubiquitin-proteasome system, which was the subject of the 2004 Nobel Prize in Chemistry awarded to A. Ciechanover, A. Hershko and I. Rose.

Having initiated a pioneering effort on the identification and validation of DUBs as targets, Hybrigenics has become a recognized leader in this field for the discovery and development of new cancer therapeutics. Hybrigenics has discovered and patented a variety of ubiquitin specific protease (USP – part of the DUB family) inhibitors, some non-specific and some specific of either USP7 or USP8, with different ranges of potency and biovailability4, 5.

Hybrigenics' expertise operates at key steps of the preclinical research chain, from target discovery to drug candidate selection including:
  • Advanced disease-relevant, cellular phenotypic assays and interference technologies,
  • High-throughput protein interaction mapping, protein networks and pathways analysis,
  • HTS-compatible, biochemical and cellular screening assays,
  • Drug-like, small molecule library screening and medicinal chemistry optimization,
  • Molecular modelling and 3D structural studies,
  • Preclinical evaluation in dedicated cellular and in vivo models.
  1. Reverdy C., Conrath S., Lopez R., Planquette C., Atamene C., Collura C., Harpon J., Battaglia V., Vivat V., Sippl W. & Colland F. Discovery of specific inihitors of human USP7/HAUSP deubiquitinating enzyme. Chem. Biol. 2012, 19(4):467-477.PMID: 22520753
  2. Sippl W., Collura V. & Colland F. Ubiquitin Specific proteases as cancer drug targets. Future Oncology 2011, 7(5):619-32. PMID: 21568678
  3. Colland F. The therapeutic potential of deubiquitinating enzyme inhibitors. Biochem Soc Trans 2010 Feb;38(Pt 1):137-43.. PMID: 20074048
  4. Colombo M., Vallese S., Peretto I., Jacq X., Rain J.C., Colland F., Guedat P. Synthesis and Biological Evaluation of 9-Oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile Analogues as Potential Inhibitors of Deubiquitinating Enzymes. ChemMedChem 2010, 5(4):552-558. PMID: 20186914
  5. Colland F, Formstecher E, Jacq X, Reverdy C, Planquette C, Conrath S, Trouplin V, Bianchi J, Aushev VN, Camonis J, Calabrese A, Borg-Capra C, Sippl W, Collura V, Boissy G, Rain JC, Guedat P, Delansorne R, Daviet L. Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther. 2009 Aug; 8(8):2286-95. Epub 2009 Aug 11. PMID: 19671755.

Partnerships +

Hybrigenics has developed an extended network of partnerships with pharmaceutical and biotechnology companies as well as with prestigious academic institutes.

Hybrigenics' research program on deubiquitinating enzymes (DUBs) is exclusively partnered with Servier in the therapeutic fields of oncology, neurology, rheumatology, ophthalmology, diabetes and cardiovascular diseases. Hybrigenics is pursuing its own research program on the biology of DUBs potentially involved in proliferative diseases outside these fields.

Other partners include:

  • Halle University, Germany
  • University of Birmingham, UK
  • University of Liverpool, UK
  • University of Florida, USA
  • University of Texas, USA

Publications +

Since 2006, Hybrigenics researchers have made multiple presentations at international conferences on ubiquitin-specific proteases (USP) and have published a large number of scientific articles & reviews in a broad range of peer-reviewed journals including:

  • Reverdy C, Conrath S, Lopez R, Planquette C, Atmanene C, Collura V, Harpon J, Battaglia V, Vivat V, Sippl W, Colland F. Discovery of Specific Inhibitors of Human USP7/HAUSP Deubiquitinating Enzyme. Chemistry & Biology, 2012, 19 (4), 467-477. PMID: 22520753
  • Sippl W, Collura V, Colland F. Ubiquitin-specific proteases as cancer drug targets. Future Oncol. 2011 May; 7(5):619-32. PMID: 21568678.
  • Gouin E, Adib-Conquy M, Balestrino D, Nahori MA, Villiers V, Colland F, Dramsi S, Dussurget O, Cossart P. The Listeria monocytogenes InlC protein interferes with innate immune responses by targeting the IkB kinase subunit IKKa. Proc Natl Acad Sci USA. 2010 Oct ; 107(40) :17333-8. PMID : 20855622.
  • Colombo M, Vallese S, Peretto I, Jacq X, Rain JC, Colland F, Guedat P. Synthesis and biological evaluation of 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile analogues as potential inhibitors of deubiquitinating enzymes. ChemMedChem. 2010 Apr 6; 5(4):552-8. PMID: 20186914.
  • Colland F. The therapeutic potential of deubiquitinating enzyme inhibitors. Biochem Soc Trans. 2010 Feb; 38(Pt 1):137-43. Review. PMID: 20074048.
  • Cholay M, Reverdy C, Benarous R, Colland F, Daviet L. Functional interaction between the ubiquitin-specific protease 25 and the SYK tyrosine kinase. Exp Cell Res. 2010 Feb 15; 316(4):667-75. Epub 2009 Nov 10. PMID: 19909739.
  • Colland F, Formstecher E, Jacq X, Reverdy C, Planquette C, Conrath S, Trouplin V, Bianchi J, Aushev VN, Camonis J, Calabrese A, Borg-Capra C, Sippl W, Collura V, Boissy G, Rain JC, Guedat P, Delansorne R, Daviet L. Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther. 2009 Aug; 8(8):2286-95. Epub 2009 Aug 11. PMID: 19671755.
  • Zhu Y, Poyurovsky MV, Li Y, Biderman L, Stahl J, Jacq X, Prives C. Ribosomal protein S7 is both a regulator and a substrate of MDM2. Mol Cell. 2009 Aug 14;35(3):316-26. PMID: 19683495.
  • Daviet L, Colland F. Targeting ubiquitin specific proteases for drug discovery. Biochimie. 2008 Feb; 90(2):270-83. Epub 2007 Sep 22. Review. PMID: 17961905.
  • Achour M, Jacq X, Rondé P, Alhosin M, Charlot C, Chataigneau T, Jeanblanc M, Macaluso M, Giordano A, Hughes AD, Schini-Kerth VB, Bronner C. The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. Oncogene. 2008 Apr 3;27(15):2187-97. Epub 2007 Oct 15. PMID: 17934516.
  • Guédat P, Colland F. Patented small molecule inhibitors in the ubiquitin proteasome system. BMC Biochem. 2007 Nov 22; 8 Suppl 1:S14. Review. PubMed PMID: 18047738.
  • Mousnier A, Kubat N, Massias-Simon A, Ségéral E, Rain JC, Benarous R, Emiliani S, Dargemont C. von Hippel Lindau binding protein 1-mediated degradation of integrase affects HIV-1 gene expression at a postintegration step. Proc Natl Acad Sci USA. 2007 Aug 21;104(34):13615-20. Epub 2007 Aug 13. PMID: 17698809.
  • Atfi A, Dumont E, Colland F, Bonnier D, L'helgoualc'h A, Prunier C, Ferrand N, Clément B, Wewer UM, Théret N. The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor. J Cell Biol. 2007 Jul 16;178(2):201-8. Epub 2007 Jul 9. PMID: 17620406.
  • Formstecher E, Reverdy C, Cholay M, Planquette C, Trouplin V, Lehrmann H, Aresta S, Calabrese A, Arar K, Daviet L, Colland F. Combination of active and inactive siRNA targeting the mitotic kinesin Eg5 impairs silencing efficiency in several cancer cell lines. Oligonucleotides. 2006 Winter;16(4):387-94. PMID: 17155913.
  • van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F, Maurice MM, Burgering BM. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nat Cell Biol. 2006 Oct; 8(10):1064-73. Epub 2006 Sep 10. PMID: 16964248.
  • Colland F. Ubiquitin and cancer: from molecular targets and mechanisms to the clinic -- AACR Special Conference. IDrugs. 2006 Mar; 9(3):179-81. PMID:16523381.